P
US7365091B2ExpiredUtilityPatentIndex 88

Derivatives of succinic and glutaric acids and analogs thereof useful as inhibitors of PHEX

Assignee: ENOBIA PHARMAPriority: Dec 3, 2002Filed: May 26, 2006Granted: Apr 29, 2008
Est. expiryDec 3, 2022(expired)· nominal 20-yr term from priority
Inventors:GRAVEL DENISRATEMI ELAREF SHATAM MOSTAFABOILEAU GUYCRINE PHILIPPELEMIRE ISABELLE
C07F 9/4006C07K 5/06191C07D 213/40C07C 233/05C07C 259/06C07K 5/06104C07D 209/20C07D 209/16C07K 5/0819C07F 9/653C07K 5/06113C07F 9/5728
88
PatentIndex Score
21
Cited by
61
References
34
Claims

Abstract

The present invention relates to derivatives of succinic and glutaric acids and analogues thereof, having the following general formula: useful as inhibitors of PHEX. These derivatives are useful for promoting generation of bone mass and treating or preventing diseases or conditions associated with a phosphate metabolism defect. Methods for preparation and intermediates are also disclosed.

Claims

exact text as granted — not AI-modified
1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 A is 
 
       
         
           
           
               
               
           
         
         B is 
       
       
         
           
           
               
               
           
         
         R is hydrogen or lower alkyl; 
         R 1  is hydrogen or lower alkyl; 
         R 2  is hydrogen, or lower alkyl; 
         R 3  is hydrogen or lower alkyl; 
         R 4  is lower alkyl, substituted lower alkyl, cycloalkyl-(CH 2 ) w —, aryl-(CH 2 ) w —, substituted aryl —(CH 2 ) w — or heteroaryl-(CH 2 ) w —; 
         R 5  is hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl-(CH 2 ) x —, aryl-(CH 2 ) x —, substituted aryl-(CH 2 ) x —, or heteroaryl-(CH 2 ) x —; 
         R 6  is hydrogen or R 7 —CO—; 
         R 7  is alkyl, substituted alkyl, cycloalkyl-(CH 2 ) y , aryl-(CH 2 ) y —, substituted aryl-(CH 2 ) y — or heteroaryl-(CH 2 ) y —; 
         R 11  is hydrogen or lower alkyl; 
         D is —COOH; 
         E is hydrogen, —COOH, —CONH 2 , —CONH(lower alkyl), —CON(lower alkyl) 2 , —CONH—(CH 2 ) 2 -aryl, —CON(—(CH 2 ) 2 -aryl) 2 , —CO-amino acid, —CH 2 COOH, CH 2 OH, —CH 2 CH 2 OH, or —COOR 16 ; 
         R 16  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl-(CH 2 ) y —, substituted aryl-(CH 2 ) y —, heteroaryl-(CH 2 ) y —, 
       
       
         
           
           
               
               
           
         
         R 13  is hydrogen, lower alkyl, cycloalkyl or phenyl; 
         R 14  is hydrogen, lower alkyl, lower alkoxy or phenyl; 
         R 15  is lower alkyl or aryl-(CH 2 ) y —; 
         C is carbon; 
         H is hydrogen; 
         O is oxygen; 
         N is nitrogen; 
         S is sulfur; 
         P is phosphorus; 
         v is zero or one; 
         w is zero or an integer ranging from 1 to 4; 
         x is an integer ranging from 0 to 4; 
         y is zero or an integer ranging from 1 to 6; and 
         z is zero, one, two, or three. 
       
     
     
       2. The compound of  claim 1 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-acetylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-propionylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-4-methyl-pentanoylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-methyl-butyrylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(3-hydroxy-2-mercapto-propionylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(3-hydroxy-2-mercapto-butyrylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-hexanoylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-4-phenyl-butyrylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-2-phenyl-acetylamino)-succinamic acid, 3-(3-Biphenyl-4-yl-2-mercapto-propionylamino)-N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-succinamic acid, 3-(3-(4-Benzyloxy-phenyl)-2-mercapto-propionylamino)-N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-[3-(4-fluoro-phenyl)-2-mercapto-propionylamino]-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-[2-mercapto-3-(4-methoxy-phenyl)-propionylamino]-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(3-cyclohexyl-2-mercapto-propionylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-[3-(1H-indol-3-yl)-2-mercapto-propionylamino]-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-naphthalen-2-yl-propionylamino]-succinamic acid, N-(1-Carboxy-2-naphthalen-2-yl-ethyl)-3-(2-mercapto-3-phenyl propionylamino)-succinamic acid, N-(1-Carboxy-2-hydroxy-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-[1-Carboxy-2-(4-hydroxy-phenyl)-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid, N-[1-Carboxy-2-phenyl-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-(2-Biphenyl-4-yl-1-Carboxy-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-(1-Benzyl-2-hydroxy-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid, 4-[1-Carboxy-2-(1H-indol-3-yl)-ethylcarbamoyl]-4-(2-mercapto-3-phenyl-propionylamino)-ethyl]-butyric acid, N-[2-(1H-indol-3-yl)-methylcarbamoyl-ethyl]-3-(2-mercapto-acetyl amino)-succinamic acid, N-[1-(1-Carboxy-2-hydroxy-ethylcarbamoyl)-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid, N-[2-(1H-indol-3-yl)-methoxycarbonyl-ethyl]-3-(2-mercapto-acetyl amino)-succinamic acid, or N-[2-(1H-indol-3-yl)1-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid. 
     
     
       3. The compound of  claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-2-phenyl-acetylamino)-succinamic acid. 
     
     
       4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a physiologically acceptable carrier or excipient. 
     
     
       5. The pharmaceutical composition of  claim 4 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-acetylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-propionylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-4-methyl-pentanoylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-methyl-butyrylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(3-hydroxy-2-mercapto-propionylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(3-hydroxy-2-mercapto-butyrylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-hexanoylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-4-phenyl-butyrylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-2-phenyl-acetylamino)-succinamic acid, 3-(3-Biphenyl-4-yl-2-mercapto-propionylamino)-N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-succinamic acid, 3-(3-(4-Benzyloxy-phenyl)-2-mercapto-propionylamino)-N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-[3-(4-fluoro-phenyl)-2-mercapto-propionylamino]-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-[2-mercapto-3-(4-methoxy-phenyl)-propionylamino]-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(3-cyclohexyl-2-mercapto-propionylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-[3-(1H-indol-3-yl)-2-mercapto-propionylamino]-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-naphthalen-2-yl-propionylamino]-succinamic acid, N-(1-Carboxy-2-naphthalen-2-yl-ethyl)-3-(2-mercapto-3-phenyl propionylamino)-succinamic acid, N-(1-Carboxy-2-hydroxy-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-[1-Carboxy-2-(4-hydroxy-phenyl)-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid, N-[1-Carboxy-2-phenyl-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-(2-Biphenyl-4-yl-1-Carboxy-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-(1-Benzyl-2-hydroxy-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid, 4-[1-Carboxy-2-(1H-indol-3-yl)-ethylcarbamoyl]-4-(2-mercapto-3-phenyl-propionylamino)-ethyl]-butyric acid, N-[2-(1H-indol-3-yl)-methylcarbamoyl -ethyl]-3-(2-mercapto-acetyl amino)-succinamic acid, N-[1-(1-Carboxy-2-hydroxy-ethylcarbamoyl)-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid, N-[2-(1H-indol-3-yl)-methoxycarbonyl-ethyl]-3-(2-mercapto-acetyl amino)-succinamic acid, or N-[2-(1H-indol-3-yl)1-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid. 
     
     
       6. The pharmaceutical composition of  claim 5 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-2-phenyl-acetylamino)-succinamic acid. 
     
     
       7. The compound of  claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-acetylamino)-succinamic acid. 
     
     
       8. The compound of  claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid. 
     
     
       9. The compound of  claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-propionylamino)-succinamic acid. 
     
     
       10. The compound of  claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-4-methyl-pentanoylamino)-succinamic acid. 
     
     
       11. The compound of  claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-methyl-butyrylamino)-succinamic acid. 
     
     
       12. The compound of  claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(3-hydroxy-2-mercapto-propionylamino)-succinamic acid. 
     
     
       13. The compound of  claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl)-3-(3-hydroxy-2-mercapto-butyrylamino)-succinamic acid. 
     
     
       14. The compound of  claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-hexanoylamino)-succinamic acid. 
     
     
       15. The compound of  claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-4-phenyl-butyrylamino)-succinamic acid. 
     
     
       16. The compound of  claim 2 , wherein the compound is further defined as 3-(3-Biphenyl-4-yl-2-mercapto-propionylamino)-N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-succinamic acid. 
     
     
       17. The compound of  claim 2 , wherein the compound is further defined as 3-(3-(4-Benzyloxy-phenyl)-2-mercapto-propionylamino)-N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-succinamic acid. 
     
     
       18. The compound of  claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-[3-(4-fluoro-phenyl)-2-mercapto-propionylamino]-succinamic acid. 
     
     
       19. The compound of  claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-[2-mercapto-3-(4-methoxy-phenyl)-propionylamino]-succinamic acid. 
     
     
       20. The compound of  claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(3-cyclohexyl-2-mercapto-propionylamino)-succinamic acid. 
     
     
       21. The compound of  claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-[3-(1H-indol-3-yl)-2-mercapto-propionylamino]-succinamic acid. 
     
     
       22. The compound of  claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-naphthalen-2-yl-propionylamino]-succinamic acid. 
     
     
       23. The compound of  claim 2 , wherein the compound is further defined as N-(1-Carboxy-2-naphthalen-2-yl-ethyl)-3-(2-mercapto-3-phenyl propionylamino)-succinamic acid. 
     
     
       24. The compound of  claim 2 , wherein the compound is further defined as N-(1-Carboxy-2-hydroxy-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid. 
     
     
       25. The compound of  claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(4-hydroxy-phenyl)-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid. 
     
     
       26. The compound of  claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-phenyl-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid. 
     
     
       27. The compound of  claim 2 , wherein the compound is further defined as N-(2-Biphenyl-4-yl-1-Carboxy-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid. 
     
     
       28. The compound of  claim 2 , wherein the compound is further defined as N-(1-Benzyl-2-hydroxy-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid. 
     
     
       29. The compound of  claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid. 
     
     
       30. The compound of  claim 2 , wherein the compound is further defined as 4-[1-Carboxy-2-(1H-indol-3-yl)-ethylcarbamoyl]-4-(2-mercapto-3-phenyl-propionylamino)-ethyl]-butyric acid. 
     
     
       31. The compound of  claim 2 , wherein the compound is further defined as N-[2-(1H-indol-3-yl)-methylcarbamoyl-ethyl]-3-(2-mercapto-acetyl amino)-succinamic acid. 
     
     
       32. The compound of  claim 2 , wherein the compound is further defined as N-[1-(1-Carboxy-2-hydroxy-ethylcarbamoyl)-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid. 
     
     
       33. The compound of  claim 2 , wherein the compound is further defined as N-[2-(1H-indol-3-yl)-methoxycarbonyl-ethyl]-3-(2-mercapto-acetyl amino)-succinamic acid. 
     
     
       34. The compound of  claim 2 , wherein the compound is further defined as N-[2-(1H-indol-3-yl)1-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid.

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